The Risk Factors Affecting Survival in Colorectal Cancer in Taiwan.

Background
Colorectal cancer is one of the most common malignancies in developed countries. The incidence of colorectal cancer (CRC) in Taiwan is rising. We aimed to determine the five-yr survival rate of patients diagnosed with CRC and determine factors affecting survival.


Methods
All patients were identified from the Taiwan Cancer Data Base of the Medical Center Hospital in North Taiwan from 2007 to 2013. Data were collected using medical records and the cancer database. In all, 869 patients with CRC were included. Survival analysis was performed using Kaplan-Meier curves, and differences between the curves were analyzed using the log-rank test. Cox proportional hazards regression models were used to analyze survival by each variable.


Results
The five-yr survival rate and the mean survival time after cancer diagnosis were 68.7% and 71.27±1.27 months. Perineural nerve invasion, distant metastasis, age, pathological differentiation grade, obstruction and regional lymph node metastasis were found to be independent predictors of the survival and prognosis of patients with CRC.


Conclusion
Perineural nerve invasion was an important factor related to the survival of CRC patients. Thus, the earlier detection of CRC might help improve survival.


Introduction
Colorectal cancer (CRC) is the second and third most commonly diagnosed cancer type in females and males, respectively, representing almost 10% of the global cancer incidence. These estimates correspond to age-standardized global incidence and mortality rates of 17.2 and 8.3 per 100000, respectively (1)(2)(3). There have been slightly more cal pathological characteristics, prognostic factors, and overall survival among 3 groups of CRC patients, i.e., those surviving 12, 36, and 60 months. This study aimed to explore the survival rate and the potential factors influencing survival among CRC patients in northern Taiwan.

Study population
We conducted a single-center, retrospective cohort study to estimate the survival outcome of patients diagnosed with colorectal carcinoma at Cathay General Hospital in North Taiwan from 2007 to 2013. Data were extracted from medical records and the cancer database by trained data collectors. The eligibility criteria included the following: diagnosis and treatment of CRC; the International Classification of Disease for Oncology, 3rd Edition (ICD-O-3) topographical codes of C18.0-C20.9 (excluding C18.1) and morphology codes of 8000-8152, 8154-8231, 8243-8245, 8247-8248, 8250-8576, 8940-8950 and 8980-8981. Participants who showed more than one type of cancer, ICD-O-3 morphology codes of 8935-8936, 8153, 8240-8242, 8013, 8246, 8249 and 9590-9720, a TXNXMX stage of 888 or 999, metastasis to the brain, or a survival time of fewer than six months were excluded. Demographic data extracted included gender, age at diagnosis, body mass index (BMI), smoking history, betel nut chewing status, drinking habits, and date of last contact or death. The evaluated tumor characteristics included primary site, histologic type, grade/differentiation, and size, as well as treatment type and regional lymph node or distant organ metastases. The disease staging was based on the American Joint Committee on Cancer (AJCC) criteria; cancer site-specific factors included CEA, circumferential resection margin (CRM), tumor regression grade, perineural nerve invasion, KRAS mutation, obstruction, and perforation. Survival data were obtained using death and date of last contact records to determine the current situation or date of death of each patient.
The study was reviewed and approved by the hospital's institutional Review Board (No. CGH-P104060). Statistical analyses were performed using SPSS software (ver. 22.0, Chicago, IL, USA). Quantitative values were compared using t-tests for independent groups. Categorical data were analyzed using the χ 2 test or Fisher's exact test. Survival probabilities were estimated at intervals of 12, 36 and 60 months from the date of diagnosis to the date of death. Survival curves were constructed using the Kaplan-Meier method, and differences were analyzed by the log-rank test. Cox proportional hazards regression models were used to analyze survival by each variable. The level of statistical significance was set at P<0.05. All reported P-values are two-tailed.

Sample characteristics
A summary of the demographic and clinical characteristics of the participants is presented in Table 1. The follow-up period continued to Dec 2015. We retrospectively evaluated 869 CRC patients from 2007 to 2013. Of these, 454 subjects were males (52.24%). Most patients ranged in age from 51 to 75 yr old (62.37%). The mean and median ages at diagnosis were 63.70 yr and 64 yr, respectively.  Approximately 63.75% of the patients were diagnosed with cancer of the colon. One-third of patients were registered as living with stage III (34.87%) cancer, and the most common histopathological type reported was adenocarcinoma (91.71%).

Survival outcome
The mean survival time was 71.27±1.27 months. CRC-specific survival was 95.3%, 79.4% and 68.7% at 1, 3 and 5 yr (Fig. 1). The five-yr survival rate for patients with stage I, II, III and IV disease was 91.20%, 82.20%, 63.20% and 21.70%, respectively (Fig. 2). Log-rank (Mantel-Cox) tests for the equality of the survival functions were conducted as well as a univariate Cox regression analysis. Combining the results of analysis of Log-rank tests and the univariate Cox regression, significant predictors of survival were the age at cancer diagnosis, tumor status, regional lymph node metastasis, distal organ metastasis, cancer stage, pathological differentiation, histopathologic type, tumor size, CRM, perineural nerve invasion, KRAS mutation, obstruction, and perforation ( Table 2 and Table  3). The Cox forward stepwise regression model revealed a significant potentially curable disease and risk of CRC death (Table 4).

Discussion
This study observed factors connected with disease survival in a population-wide cohort with access to universal healthcare with a specific focus on recognizing the five-yr survival rate and risk factors of CRC. In a Taiwanese populationbased sample of patients with stage I-IV CRC, overall cancer survival reached 71.27±1.27 months. Certain characteristics related to disease progression were strongly associated with the 5yr risk of death from CRC: age ≥ 65 yr, high grade of pathological differentiation, perineural nerve invasion, distant metastasis, obstruction and multiple regional lymph node metastases each independently increased the risk of death by factors of 1.38 to almost 3. No correlations were found in this study between characteristic variables (e.g., BMI or smoking, drinking, betel nut chewing habits) and CRC survival. CRC was more common in men than women in our study, which was in agreement with the agespecific incidence rates reported by the Taiwan Health Promotion Administration in 2013. The median age in our study was 64 yr old; however, this age is slightly lower than that observed from cases during 2013, where the mean age of CRC patients was 66 yr (8). The five-yr survival rate found in this study was higher than (12) who reported a survival rate of 55.70% among patients with CRC. This result is probably due to differences in the study populations, as the majority of patients in their study were ≥65 yr old. By age group, the five-yr survival rate was 76.50% in patients younger than 65 and 60.90% in patients ≥ 65 yr old (P<0.001). After adjustment with the relevant control variables, we found that being ≥ 65 yr old was associated with a relative excess hazard for death of 2.36 (95% CI: 1.76-3.17, P<0.001). Similarly, patient age at diagnosis appears to be an important prognostic factor for all patients (12,19,20). In our study, we found that nearly 17% of the patients were younger than 50 yr old, with a minimum age of 17 yr. It is important to note the occurrence of CRC at a young age in our population. Patients younger than 50 yr would not yet qualify for screening and would be more likely to present with symptomatic disease and have a poorer prognosis (21). Therefore, reducing the age at which patients should be screened for this condition could lead to improved outcomes. Such strategies as fecal occult blood testing using immunochemical methods could easily be implemented. The overall five-yr survival rate in our study was 68.70%; this result is better than that reported by the HPA (8), in Taiwan (12), and the American Cancer Society, which estimated survival rates of 63.0%, 55.69%, and 66%, respectively. In our study, the overall stage-specific five-yr survival rate was 91.20% for stage I, 82.20% for stage II, 63.20% for stage III, and 21.70% for stage IV. Stage I and stage II CRC had an 80%-90% five-yr survival rate, whereas stage III and stage IV metastatic diseases were associated with five-yr survival rates of 60% and 8%, respectively (10). In comparison, the survival rates found in the present study were higher than those previously reported.  (26,28,29). Early CRC staging has a positive effect on survival rate. Therefore, the earlier detection of CRC should lead to substantial improvements in survival. CRC screenings were at < 50 yr of age (12,19,24). In the present study, the univariate analysis revealed that histology type was a significant factor. There were significant percentages of mucinous adenocarcinoma (7.36%) and signet ring cell carcinoma (0.92%). These findings are similar to those of previous CRC studies (12,24,28). The risk of death in mucinous adenocarcinoma and signet ring-cell CRC with adenocarcinoma was 1.77 (95% CI: 1.16-2.71, P=0.008) and 2.80 (95% CI: 1.04-7.55, P=0.042), respectively. The histology type of CRC was a risk factor for survival rate (12,28). However, in the forward stepwise Cox regression analysis, histology type did not independently affect the survival rate of CRC patients.
In this study, perineural nerve invasion was associated with a relative excess hazard for death of 4.43 (95% CI: 3.22-6.10, P<0.001). Furthermore, our forward stepwise Cox regression analysis showed that perineural nerve invasion was associated with improved predictions of CRC prognosis, which was in agreement with previous reports (12,(30)(31)(32). After adjustment with the relevant control variables, peripheral nerve invasion remained an independent predictor of patient survival and prognosis. The importance of this factor should be considered by clinicians when assessing the prognosis of patients.
Obstruction was a significant factor affecting the survival of CRC patients. In the present study, the univariate Cox regression analysis demonstrated better survival in patients without obstruction (HR = 1.87, 95% CI: 1.43-2.44, P<0.001). After adjustment with the relevant control variables, obstruction was associated with a relative excess hazard for death of 1.38 (95% CI: 1.04-1.84, P=0.026). These findings are similar to other studies (33,34). One limitation of this study was the small sample size; in addition, the findings were generated using data from a single medical center hospital in North Taiwan. Thus, the results of some survival comparisons were not significant. These limitations should be considered when applying these results to other districts in Taiwan that may have demographic differences. Furthermore, multicenter studies should be conducted to merge patient datasets for further research in Taiwan.

Conclusion
There are numerous prognostic parameters affecting survival in colorectal cancers. Presence of perineural nerve invasion, distant metastasis, age, pathological differentiation grade, obstruction and regional lymph node metastasis are independent predictors of the survival and prognosis of patients with CRC. Perineural nerve invasion and distant metastasis appeared to be important prognostic factors affecting the entire patient cohort. Therefore, the earlier detection of CRC should lead to substantial improvements in survival.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.